The ARQ 197-215 study randomized patients to tivantinib or placebo and pre-specified efficacy analyses indicated the predictive value of MET expression as a marker of benefit from tivantinib in hepatocellular carcinoma (HCC). We aimed to explore the neutrophil-to-lymphocyte ratio (NLR) in 98 ARQ 197-215 patients with available absolute neutrophil count and absolute lymphocyte count at baseline. The cut-off value used to define high versus low NLR was 3.0. In univariate analysis, high NLR was associated with hazard ratio (HR) for overall survival (OS) of 1.58 [95% confidence interval (CI) 1.01; 2.47; P <0.046], corresponding to median OS of 5.1 months versus 7.8 months in patients with low NLR (P = 0.044). In contrast, time to progression was not significantly affected by NLR (P = 0.20). Multivariable model confirmed that both NLR >3 (P = 0.03) and presence of vascular invasion (P = 0.017) were negatively associated with OS. After adjustment for vascular invasion, NLR independently predicted survival in both the placebo and the tivantinib cohort. For OS, no interaction was detected between NLR status and treatment (Pinteraction = 0.40). Baseline NLR is an independent prognostic biomarker in patients with HCC and compensated liver function who are candidate for second-line treatments.